31 July 2006. This is part 1 of our 3-part series. Also see part 2 and part 3 or download PDF.
Immunotherapy may not be the most eclectic choice of subject for those news aficionados who thirst for something completely different. Yet as the bearer of much hope and expectation throughout the field, the topic clearly warrants an update from every conference that offers news. And news there was at the 10th International Conference on Alzheimer’s Disease and Related Disorders, held July 15 to 20 in Madrid. Here is a quick summary of some of the presentations this reporter managed to attend. Whip out your notes, and send in additions or corrections! (And for those who still want something completely different, check out our closing story, in part 3 of this series, of Beka Solomon’s phage-only nose spray.)
Remains of AN1792—did it do some good, after all?
Followers of the field have heard proponents repeat the refrain that the trial of Elan/Wyeth’s active immunotherapy prototype was valuable despite the aseptic meningoencephalitis that halted it prematurely. Skeptics might say: “Yes, yes, we’ve heard that the trial proved immunotherapy can remove Aβ from human brain. And yes, we know that the responders of the Zurich cohort appear to be doing a tad better than the non-responders even if that’s but a handful of people.” But what most may not know yet is that an ongoing follow-up study of the entire trial population is beginning to show inklings that the same may be true throughout.
Mike Grundman, who formerly worked at the University of California, San Diego site of the Alzheimer Disease Cooperative Study (ADCS) and now is at Elan Pharmaceuticals in South San Francisco, heads the study. UCSD’s Leon Thal, who is chief investigator of the ADCS, encouraged Elan/Wyeth to conduct the study and presented the data available to date. At a packed symposium sponsored by Elan, Thal first reminded the audience that the trial participants, who received one or two injections of antigen, showed a small but significant improvement in three memory and three executive function tests (Gilman et al., 2005). But how well they fare beyond this assessment is unknown. Indeed, for a while scientists worried that there would not be any formal follow-up study of the trial participants. This study now under way asks these questions:
- How are the participants doing clinically in the long term?
- Do their antibody titers persist?
- Do their puzzling MRI findings persist?
- Did they develop anymore side effects after the study ended?
The study began this past January, 4.5 years after the trial began. It is being conducted blinded. Participants who are still able to visit the clinics are asked to come in, while others receive home visits or phone calls from investigators. Many of the study participants have progressed in their AD so that neuropsychological testing is no longer possible. For this reason, the investigators are applying a dependence scale and interviews with caregivers instead, though neuropsychology tests and MRI scans are still taken where possible. To date, about 40 percent of the original study—372 participants—have been contacted, and 85 of them agreed to participate. “We expect to have twice the data eventually that we have now,” Thal said.
What does that initial data suggest? This long after the trial, the mean MMSE for the treated group is 13, and for those on placebo it is 10. Both groups started out at a mean of 20. Seven of the eight responders (defined as people who produced antibodies in response to the vaccine) whose blood has been tested so far have retained “respectable” titers, Thal said. Ninety-five percent of placebo recipients now require total care, whereas 65 percent of the responders do. On activities of daily living, all groups declined comparably, and the clinical dementia rating (CDR) changed for the worse in all groups, as well. The ADAS-Cog data are too premature to make a statement, Thal noted. Follow-up MRI scans are slowly trickling in; the two available to date from the placebo group and three from the responder group no longer show the differential brain shrinkage that had startled the field after an initial post-dose scan (see Fox et al., 2005). There, too, the data is too premature to make a claim, Thal cautioned.
A curious finding popped up around the basic measure of age. At baseline, both treatment and placebo groups had a mean age of just over 71. At the 2006 follow-up, the treatment group had aged, as one would expect, to a mean age of 76; however, the placebo recipients who have been contacted so far still come in at a mean age of 71. Time has not stood still for them; rather, it is possible that the older AD patients among the placebo group might have died at a higher rate than those in the treatment group.
Finally, no further cases of encephalitis beyond the 18 reported ones have cropped up since then, nor did other drug-related serious side effects, Thal noted. He emphasized that even though the data show a trend favoring patients who received AN1792 and responded to it, this data is highly preliminary and not yet fit for conclusions.
For his part, Roger Nitsch of University of Zurich offered further tidbits of data on the AN1792 trial Zurich cohort that his group is following separately. On the meningoencephalitis, Nitsch noted that of the three Zurich patients who developed it, two have antibodies and their Alzheimer disease remains stable to date, whereas one did not have antibodies and died three years after the immunization.
Nitsch then described a fourth autopsy case in addition to three published ones, from Southampton (Nicoll et al., 2003), Barcelona (Ferrer et al., 2004), and Arizona (Masliah et al., 2005). A 79-year-old man with a 7-year history of dementia from the Zurich group stopped speaking after a final MMSE of 12, then died four years after having received two shots of vaccine. He did not suffer the encephalitis and had low antibody titers in his blood and CSF. His Aβ levels in frontal and temporal cortex were low, as was amyloid deposition, Nitsch reported. Amyloid plaques had microglia around them, which stained with the 6E10 Aβ antibody, indicating the cells were ingesting the amyloid. This patient showed severe neuronal loss, gliosis, but no cerebral amyloid angiopathy. Alzforum has followed conference updates on this trial closely; for recent news, see ARF Eibsee report; ARF Sorrento story; and ARF St. Moritz story).—Gabrielle Strobel.